Glomerular hyperfiltration in microalbuminuric NIDDM patients

Summary Glomerular hyperfiltration and microalbuminuria are both regarded as risk factors for the development of diabetic nephropathy in insulin-dependent diabetic patients. Information on glomerular hyperfiltration is scarse in microalbuminuric non-insulin-dependent diabetic (NIDDM) patients. Therefore, we performed a cross-sectional study of glomerular filtration rate (single i. v. bolus injection of ⁵¹Cr-EDTA, plasma clearance for 4 h) in 158 microalbuminuric NIDDM patients compared to 39 normoalbuminuric NIDDM patients and 20 non-diabetic control subjects. The groups were well-matched with regard to sex, age and body mass index. The uncorrected (ml/min) and the adjusted (ml · min^–1· 1.73 m^–2) glomerular filtration rate were both clearly elevated in the microalbuminuric patients: 139 ± 29 and 117 ± 24 as compared to 115 ± 19 and 99 ± 15; 111 ± 23 and 98 ± 21 in normoalbuminuric NIDDM patients and control subjects, respectively (p < 0.001). The glomerular filtration rate (ml · min^–1· 1.73 m^–2) in NIDDM patients who had never received antihypertensive treatment was also clearly elevated in the microalbuminuric patients (n = 96): 119 ± 22 as compared to 100 ± 14 and 98 ± 21 in normoalbuminuric NIDDM patients (n = 27) and control subjects (n = 20), respectively (p < 0.001). Glomerular hyperfiltration (elevation above mean glomerular filtration rate plus 2 SD in normoalbuminuric NIDDM patients) was demonstrated in 37 (95 % confidence interval 30–45)% of the microalbuminuric patients. Multiple regression analysis revealed that HbA_{1 c}, 24-h urinary sodium excretion, age and known duration of diabetes were correlated with glomerular filtration rate in microalbuminuric NIDDM patients (r ² = 0.21, p < 0.01). Our cross-sectional study indicates that NIDDM patients at high risk of developing diabetic nephropathy are also characterized by an additional putative risk factor for progression, glomerular hyperfiltration. [Diabetologia (1996) 39: 1584–1589]     

The clinical course of renal function in NIDDM patients with normo- and microalbuminuria

Objectives. To assess the clinical course of renal function in relation to risk factors in NIDDM patients with normo- and microalbuminuria. Design. Prospective clinical study. Setting. Outpatient diabetic clinic. Subjects. Thirty-two NIDDM patients with normo- or microalbuminuria followed for (mean (range)) 5.5 (3.3–7.5) years. Main outcome measures. Glomerular filtration rate, urinary albumin excretion rate, blood pressure, lipids, glycaemic control. Results. The mean rate of decline of glomerular filtration rate was ?1.2±2.3 (mean±SD) (95% confidence intervals: ?2.0–?0.3) mL min^?1 1.73 m^?2 year^?1 (p=0.009). A considerable interindividual variation was observed (range ?6.7 to +3.4 mL  min^?1 1.73 m^?2 year^?1). No difference was found between normo- and microalbuminuric patients (?1.2±0.5 vs. ?1.0±0.7 mL min^?1 1.73 m^?2 year^?1) or between patients with and without antihypertensive treatment (?1.7±0.7 vs. ?0.7±0.4  mL min^?1 1.73 m^?2 year^?1). By multiple linear regression analysis the fall rate of glomerular filtration was determined by the mean glomerular filtration rate level (p=0.036). Analysis of patients without antihypertensive treatment revealed that urinary albumin excretion rate and HbA_1c levels significantly determined the fall rate of glomerular filtration (P<0.001 and=0.014). Conclusions. The average decline in renal function of these normo- and microalbuminuric NIDDM patients was not increased as compared to the age related fall rate of healthy subjects but varied markedly. Low glomerular filtration rate is associated with a higher fall rate. In patients without antihypertensive treatment higher urinary albumin excretion rate, and poorer glycaemic control are factors associated with an increased fall rate of glomerular filtration.     

Urinary Excretion and Clearance of Insulin in Diabetic and Normal Children and Adolescents

Seventy-two diabetic (38 males) and 86 normal (41 males) children provided timed overnight urine collections. Fourteen of the diabetic and 33 of the normal children had concurrent overnight plasma insulin profiles. Urinary insulin clearance in the diabetic subjects was compared with excretion of albumin, growth hormone, retinol-binding protein, and N-acetyl-β-D -glucosaminidase. In the normal subjects, urinary insulin excretion correlated with mean overnight plasma levels in the boys (r = 0.82, p< 0.001) but not in the girls (r = 0.32), and varied with puberty stage in the boys. Insulin clearance was greater in boys than girls during puberty, and fell in both sexes with advancing puberty. Insulin excretion was greater in diabetic than normal children in both sexes at all puberty stages. Insulin clearance was also greater in diabetic than normal subjects (1.05 ± 0.1 ml min^?1 1.73 m^?2 vs o.48 ± 0.05 ml min^?1 1.73 m^?2, p< 0.001). Insulin excretion as a percentage of the filtered load was also greater in diabetic than normal subjects (1.9 ± 0.27% vs 0.85 ±0.09%, p < 0.01). In the diabetic children, there was a correlation between urinary insulin and growth hormone excretion (r = 0.52, p < 0.02), and retinol-binding protein in those (n = 10) with higher retinol binding protein excretion (r = 0.76, p = 0.01). The value of urinary insulin excretion as a measure of free plasma insulin levels in normal and diabetic children may be limited by sex differences in renal insulin clearance, and by proximal renal tubular dysfunction in children with diabetes.     

Insulin resistance and abnormal albumin excretion in non-diabetic first-degree relatives of patients with NIDDM

Summary Microalbuminuria has recently been associated with insulin resistance in both insulin-dependent and non-insulin-dependent (NIDDM) diabetes mellitus. To establish whether microalbuminuria in non-diabetic subjects as well is associated with insulin resistance and associated abnormalities in glucose and lipid metabolism, oral glucose tolerance tests were performed with measurement of urinary albumin excretion rate, lipids and lipoproteins in 582 male non-diabetic first-degree relatives of patients with NIDDM. In addition, insulin sensitivity was assessed in 20 of these subjects with the euglycaemic hyperinsulinaemic clamp technique. Abnormal albumin excretion rate (AER), defined as AER 15–200 g/min, was associated with higher systolic blood pressure (p<0.05), higher fasting glucose values (p<0.05), lower HDL-cholesterol (p<0.05) and lower apolipoprotein A-I (p<0.05) concentrations than observed in subjects with normal AER. The rate of glucose metabolism was lower in subjects with abnormal compared to subjects with normal albumin excretion rate (38.0±2.8 vs 47.3±2.4 mol·kg lean body mass^–1. min^–1; p=0.028). This difference was almost completely accounted for by a reduction in non-oxidative glucose metabolism (17.7±1.9 vs 27.4±2.7 mol·kg lean body mass^–1. min^–1; p = 0.010), which correlated inversely with the AER (r=–0.543; p=0.013). These results suggest that in non-diabetic individuals genetically predisposed to NIDDM, abnormal AER is associated with insulin resistance and abnormalities in glucose and lipid metabolism.Abbreviations LBM lean body mass - IDDM Insulin-dependent diabetes mellitus - HDL high-density lipoprotein - NIDDM non-insulin-dependent diabetes mellitus - VLDL very low density lipoprotein - AER albumin excretion rate - OGTT oral glucose tolerance test     

Thrombomodulin Levels in Insulin-dependent Diabetic Patients with Microalbuminuria

Thrombomodulin (TM) plays an important role in the regulation of blood coagulation at the endothelial surface. TM is also present in plasma, where an increase of its level seems to reflect endothelial damage. Since microalbuminuria is associated with an increased atherothrombotic risk and is considered an expression of widespread vascular damage, we evaluated plasma thrombomodulin levels, blood pressure, and plasma lipid values in Type 1 diabetic patients with micro- and normoalbuminuria. Thrombomodulin was measured in 12 microalbuminuric (albumin excretion rate 20–200 μg min^?1 in 2 of 3 overnight urine collections) and in 12 normoalbuminuric (albumin excretion rate < 20 μg min^?1) Type 1 diabetic patients matched for age, sex, body mass index, smoking habits, diabetes duration, and glycated haemoglobin. Mean thrombomodulin was significantly higher in micro- than in normalbuminuric group (59.34 ± 3.58 vs 43.56 ± 3.52 ng ml^?1 p < 0.01). Systolic and diastolic blood pressure were significantly higher in micro- than in normoalbuminuric group (p < 0.05). There was a positive correlation between plasma thrombomodulin and albumin excretion rate (p = 0.013, r = 0.49), and between thrombomodulin and diastolic blood pressure (p = 0.023, r = 0.46) in diabetic patients as a whole but not in the individual groups. These findings suggest the presence of an endothelial injury in microalbuminuric patients.     

A missense mutation of the muscle glycogen synthase gene (M416V) is associated with insulin resistance in the Japanese population

Summary Muscle glycogen synthase (GYS1) is a key enzyme of non-oxidative pathway of glucose metabolism that has been reported to be related to insulin resistance in non-insulin-dependent diabetic (NIDDM) patients. We scanned the GYS1 gene for mutation by single strand conformational polymorphism in 244 non-obese Japanese NIDDM patients and 181 non-diabetic control subjects, and found two missense mutations; Met to Val at position 416 in the exon 10 (M416V) and Pro to Ala at position 442 in the exon 11 (P442A). The P442A mutation was found in only one NIDDM patient treated with sulfonylureas. On the other hand, the M416V mutation was widely found in the Japanese population. The mutant allele frequency in the NIDDM patients (13.7 %) was slightly higher but not statistically significant compared with that in non-diabetic subjects (9.7 %). However, the insulin sensitivity index [SI: × 10^{− 4}× min^{− 1}× (μU/ml)^{− 1}] estimated by Minimal Model analysis in the NIDDM patients carrying the M416V mutation was significantly lower than that in those without the mutation (1.18 ± 0.27, n = 21 vs 2.20 ± 0.20, n = 60, mean ± SEM, p < 0.01). Glucose effectiveness, age, body mass index, and levels of glycated haemoglobin and serum lipids were not significantly different between the two groups. The same trend could be seen in non-diabetic subjects (SI: 3.70 ± 0.46, 9 subjects with the mutation vs 5.94 ± 0.66, 19 subjects without the mutation, p < 0.05). These findings indicate that the M416V mutation of the GYS1 gene is one of the factors contributing to the insulin resistance in the Japanese population and may play some role in the pathogenesis of NIDDM. [Diabetologia (1997) 40: 947–952] Received: 7 February 1997 and in revised form: 10 April 1997     

Post-exercise Albuminuria Does Not Predict Microalbuminuria in Type 1 Diabetic Pantients

To investigate whether post-exercise urinary albumin excretion in Type 1 diabetic children and adolescents may prospectively predict the development of microalbuminuria, we have assessed post-exercise urinary albumin excretion before and after 6.2 ± 1.7 years of follow-up in 66 diabetic children and adolescents. Post-exercise urinary albumin excretion rose significantly above the pre-exercise values in diabetic patients by 2.7 (-3.8 to 84.2) μ min^?1 (p < 0.001) and in a group of 9 healthy individuals by 3.9 (-0.7 to 13.7) μg min^?1 (p < 0.02) without significant differences betbeen groups. Post-exercise albuminuria was greater in postpubertal than prepubertal 9.8 vs 4.3 μg min^?1 (p < 0.03) and pubertal 9.8 vs 6.0 μg min^?1 (p < 0.02) patients; post-exercise changes in urinary albumin excretion were also positively related to glycated haemoglobin (r = 0.293; p < 0.05). Eight out of 66 patients developed microalbuminuria at follow-up. Urinary albumin excretion at follow-up was comparable between patients with normal and abnormal post-exercise urinary albumin excretion; moreover post-exercise urinary albumin excretion was within the normal range in 5 out of 8 patients with microalbuminuria at follow-up. In conclusion post-exercise albuminuria does not seem to be a useful predictor of the onset of microalbuminuria in Type 1 diabetic children and adolescents.     

Non-invasive tracing of liver intermediary metabolism in normal subjects and in moderately hyperglycaemic NIDDM subjects. Evidence against increased gluconeogenesis and hepatic fatty acid oxidation in NIDDM

Summary To test whether gluconeogenesis is increased in non-insulin-dependent diabetic (NIDDM) patients we infused (post-absorptive state) healthy subjects and NIDDM patients with [6,6-²H₂]glucose (150 min) and [3-¹³C]lactate (6 h). Liver glutamine was sampled with phenylacetate and its labelling pattern determined (mass spectrometry) after purification of the glutamine moiety of urinary phenylacetylglutamine. After correction for ¹³CO₂ re-incorporation (control test with NaH¹³CO₃ infusion) this pattern was used to calculate the dilution factor (F) in the hepatic oxaloacetate pool and fluxes through liver Krebs cycle. NIDDM patients had increased lactate turnover rates (16.18 ± 0.92 vs 12.14 ± 0.60 μmol · kg⁻¹· min⁻¹, p < 0.01) and a moderate rise in glucose production (EGP) (15.39 ± 0.87 vs 12.52 ± 0.28 μmol · kg⁻¹· min⁻¹, p = 0.047). Uncorrected contributions of gluconeogenesis to EGP were 31 ± 3 % (control subjects) and 17 ± 2 % (NIDDM patients). F was comparable (1.34 ± 0.02 and 1.39 ± 0.09, respectively) and the corrected percent and absolute contributions of gluconeogenesis were not increased in NIDDM (25 ± 3 % and 3.8 ± 0.5 μmol · kg⁻¹· min⁻¹) compared to control subjects (41 ± 3 % and 5.1 ± 0.4 μmol · kg⁻¹· min⁻¹). The calculated pyruvate carboxylase over pyruvate dehydrogenase activity ratio was comparable (12.1 ± 2.6 vs 11.2 ± 1.4). Lastly hepatic fatty oxidation, as estimated by the model, was not increased in NIDDM (1.8 ± 0.4 vs 1.6 ± 0.1 μmol · kg⁻¹· min⁻¹). In conclusion, in the patients studied we found no evidence of increased hepatic fatty oxidation, or, despite the increased lactate turnover rate, an increased gluconeogenesis. [Diabetologia (1998) 41: 212–220] Received: 4 July 1997 and in revised form: 16 September 1997     

Risk and mechanism of dexamethasone-induced deterioration of glucose tolerance in non-diabetic first-degree relatives of NIDDM patients

Summary We tested the hypothesis that glucose intolerance develops in genetically prone subjects when exogenous insulin resistance is induced by dexamethasone (dex) and investigated whether the steroid-induced glucose intolerance is due to impairment of beta-cell function alone and/or insulin resistance. Oral glucose tolerance (OGTT) and intravenous glucose tolerance tests with minimal model analysis were performed before and following 5 days of dex treatment (4 mg/day) in 20 relatives of non-insulin-dependent diabetic (NIDDM) patients and in 20 matched control subjects (age: 29.6 ± 1.7 vs 29.6 ± 1.6 years, BMI: 25.1 ± 1.0 vs 25.1 ± 0.9 kg/m²). Before dex, glucose tolerance was similar in both groups (2-h plasma glucose concentration (PG): 5.5 ± 0.2 [range: 3.2–7.0] vs 5.5 ± 0.2 [3.7–7.4] mmol/l). Although insulin sensitivity (Si) was significantly lower in the relatives before dex, insulin sensitivity was reduced to a similar level during dex in both the relatives and control subjects (0.30 ± 0.04 vs 0.34 ± 0.04 10^–4 min^–1 per pmol/l, NS). During dex, the variation in the OGTT 2-h PG was greater in the relatives (8.5 ± 0.7 [3.9–17.0] vs 7.5 ± 0.3 [5.7–9.8] mmol/l, F-test p < 0.05) which, by inspection of the data, was caused by seven relatives with a higher PG than the maximal value seen in the control subjects (9.8 mmol/l). These “hyperglycaemic” relatives had diminished first phase insulin secretion (?1) both before and during dex compared with the “normal” relatives and the control subjects (pre-dex ?1: 12.6 ± 3.6 vs 26.4 ± 4.2 and 24.6 ± 3.6 (p < 0.05), post-dex ?1: 22.2 ± 6.6 vs 48.0 ± 7.2 and 46.2 ± 6.6 respectively (p < 0.05) pmol · l^–1· min^–1 per mg/dl). However, Si was similar in “hyperglycaemic” and “normal” relatives before dex (0.65 ± 0.10 vs 0.54 ± 0.10 10−4 · min^–1 per pmol/l) and suppressed similarly during dex (0.30 ± 0.07 vs 0.30 ± 0.06 10−4 · min^–1 per pmol/l). Multiple regression analysis confirmed the unique importance of low pre-dex beta-cell function to subsequent development of high 2-h post-dex OGTT plasma glucose levels (R ² = 0.56). In conclusion, exogenous induced insulin resistance by dex will induce impaired or diabetic glucose tolerance in those genetic relatives of NIDDM patients who have impaired beta-cell function (retrospectively) prior to dex exposure. These subjects are therefore unable to enhance their beta-cell response in order to match the dex-induced insulin resistant state. [Diabetologia (1997) 40: 1439–1448] Received: 20 January 1997 and in final revised form: 17 July 1997     

A Prospective Study of Clinical and Metabolic Associates of Proteinuria in Patients with Type 2 Diabetes Mellitus

Urinary protein excretion rate and clinical and metabolic associates were investigated in a group of 108 patients with Type 2 diabetes mellitus at the time of diagnosis and after 5 years, and also 121 control subjects. The presence of coronary heart disease, neuropathy and retinopathy, cardiovascular risk factors and 24-h urinary excretion rate of albumin, beta-2-microglobulin, and IgG were examined. At the 5-year examination, urinary excretion rate of albumin was higher in diabetic patients than in control subjects (39 ± 75 vs 16 ± 28 mg 24 h^?1 for men, p < 0.05; 38 ± 57 vs 22 ± 42 mg 24^?1 h for women, p < 0.01). Furthermore, increased beta-2-microglobulin excretion rate, a marker of tubular impairment, was observed in diabetic men as compared to control men (0.17 ± 0.15 vs 0.14 ± 0.21 mg 24 h^?1, p < 0.05). Diabetic patients with increased albumin excretion rate (> 30 mg 24 h^?1) showed poorer metabolic control than those with normal albumin excretion rate, but no significant differences in body mass index or in the frequencies of smoking, hypertension, coronary heart disease or retinopathy and neuropathy were observed between the groups. Baseline hyperinsulinaemia was closely associated with increasing albuminuria at the 5-year examination.     

Renal function and insulin sensitivity during simvastatin treatment in Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria

Summary The effect of simvastatin (10–20 mg/day) on kidney function, urinary albumin excretion rate and insulin sensitivity was evaluated in 18 Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria and moderate hypercholesterolaemia (total cholesterol ≥5.5 mmol·l⁻¹). In a double-blind, randomized and placebo-controlled design treatment with simvastatin (n=8) for 36 weeks significantly reduced total cholesterol (6.7±0.3 vs 5.1 mmol·l⁻¹ (p<0.01)), LDL-cholesterol (4.4±0.3 vs 2.9±0.2 mmol·l⁻¹ (p<0.001)) and apolipoprotein B (1.05±0.04 vs 0.77±0.02 mmol·l⁻¹ (p<0.01)) levels as compared to placebo (n=10). Both glomerular filtration rate (mean±SEM) (simvastatin: 96.6±8.0 vs 96.0±5.7 ml·min⁻¹·1.73 m⁻², placebo: 97.1±6.7 vs 88.8±6.0 ml·min⁻¹·1.73 m⁻²) (NS) and urinary albumin excretion rate (geometric mean x/÷ antilog SEM) (simvastatin: 18.4x/÷1.3vs 16.2 x/÷1.2 μg·min⁻¹, placebo 33.1 x/÷ 1.3 vs 42.7 x/÷ 1.3 μg·min⁻¹)(NS) were unchanged during the study. A euglycaemic hyperinsulinaemic clamp was performed at baseline and after 18 weeks in seven simvastatin-and nine placebo-treated patients. Isotopically determined basal and insulin-stimulated glucose disposal was similarly reduced before and during therapy in both the simvastatin (2.0±0.1 vs 1.9±0.1 (NS) and 3.1±0.6 vs 3.1±0.7 mg·kg⁻¹·min⁻¹ (NS)) and the placebo group (1.9±0.1 vs 1.8±0.1 (NS) and 4.1±0.6 vs 3.8±0.2 mg·kg⁻¹·min⁻¹ (NS)). No different was observed in glucose storage or glucose and lipid oxidation before and after treatment. Further, the suppression of hepatic glucose production during hyperinsulinaemia was not influenced by simvastatin (−0.7±0.8 vs −0.7±0.5 mg·kg⁻¹·min⁻¹ (NS)). In conclusion, despite marked improvement in the dyslipidaemia simvastatin had no impact on kidney function or urinary albumin excretion rate and did not reduce insulin resistance in these microalbuminuric and moderately hypercholesterolaemic Type 2 diabetic patients.     

Plasminogen Activator Inhibitor (PAI-1) Activity is Elevated in Asian and Caucasian Subjects with Non-insulin-dependent (Type 2) Diabetes but not in Those with Impaired Glucose Tolerance (IGT) or Non-diabetic Asians

In order to study the plasminogen activator inhibitor activity (PAI-1) in subjects at different risk of non-insulin-dependent diabetes and ischaemic heart disease we examined 89 subjects with diet controlled NIDDM (49 Caucasian, 40 Asian), 29 with impaired glucose tolerance (IGT) (13 Caucasian, 16 Asian), and 149 with normal glucose tolerance (67 Caucasian, 82 Asian). Diabetes was diagnosed by WHO criteria and highly specific, monoclonal antibody-based assays were used to measure insulin, intact proinsulin, and des 31,32 proinsulin. Subjects with NIDDM were significantly more obese, had more central distribution of obesity, higher fasting plasma specific insulin concentrations (NIDDM median 74 pmol l⁻¹ vs IGT 41 pmol l⁻¹, p < 0.01 and vs normals 34 pmol l⁻¹, p < 0.001) and higher PAI-1 activity than normals and those with IGT (NIDDM 23.0 ± 6.9 vs IGT 16.8 ± 5.0, p < 0.001 and vs normals 17.1 ± 6.9 AU ml⁻¹, p < 0.001). However, PAI-1 activity was not significantly different between Asian and Caucasian normals (17.5 ± 7.3 vs 16.5 ± 6.4 AU ml⁻¹, p = ns) and diabetic (22.8 ± 7.3 vs 23.1 ± 6.6 AU ml⁻¹, p = ns) subjects. In addition to relationships with obesity and plasma triglyceride, PAI-1 activity, after controlling for age, sex, body mass index, and waist–hip ratio, was related to fasting insulin (partial r = 0.22, p < 0.001), intact proinsulin (partial r = 0.36, p < 0.001), and des 31,32 proinsulin concentrations (partial r = 0.33, p < 0.001) as measured by highly specific assays. The association of PAI-1 with diabetes was weakened but remained statistically significant (p = 0.042) after controlling for age, sex, ethnicity, obesity, plasma triglyceride, and all insulin-like molecules. We conclude that, although PAI-1 activity is raised in subjects with diet-treated NIDDM, it is normal in subjects with IGT and non-diabetic Asians, populations at high risk of NIDDM and ischaemic heart disease. Raised PAI-1 activity may play an important role in the pathogenesis of macrovascular disease in subjects with NIDDM, but is unlikely to explain excess risk of ischaemic heart disease in Asians and those with impaired glucose tolerance.     

Procoagulant activity and intimal dysfunction in IDDM

Summary The biological activity of thrombin and coagulation factor Xa was assessed in 62 insulin-dependent diabetic patients. A group of non-diabetic subjects of comparable age and urinary albumin excretion rate (<30 mg/24 h) served as control subjects (group 1,n=14). The patients were divided into three groups according to urinary albumin excretion rate. In group 2, albumin excretion rate was less than 30 mg/24 h (n=17), in group 3 albumin excretion rate was in the range 30–300 mg/24 h (n=20) and in group 4 albumin excretion rate was greater than 300 mg/24 h (n=25). Compared to non-diabetic control subjects an increase in the biological activity of factor Xa was observed in all groups of diabetic patients (prothrombin fragment 1+2 levels were 1.14±0.38 nmol/l in group 2,p<0.005; 1.06±0.45 nmol/l in group 3,p<0.05 and 1.03±0.31 nmol/l in group 4,p<0.05 vs 0.75±0.34 nmol/l in group 1). No difference in the level of antithrombin III was seen between the groups. We reconfirmed the presence of intimal dysfunction in diabetic nephropathy demonstrated by elevated transcapillary escape rate of albumin in group 4 compared with group 2 (8.9±2.0% vs 7.0±1.9%,p<0.05). An overall positive correlation between transcapillary escape rate and prothrombin fragment 1+2 was found (r=0.36,p<0.005). However, in the groups with elevated albumin excretion rate such a correlation was not significant (group 3:r=0.15,p=0.54; group 4:r=0.03,p=0.86) while it was sustained in the groups with albumin excretion rate of less than 300 mg/24 h (group 1:r=0.61,p<0.05; group 2:r=0.64,p<0.05). In conclusion, IDDM patients had elevated biological activity of factor Xa, demonstrated by elevated levels of prothrombin fragment 1+2. This increment could not be explained by a deficiency of antithrombin III. [Diabetologia (1995) 38: 73–78]     

Relationship Between Blood Pressure and Urinary Albumin Excretion Rate in Young Danish Type 1 Diabetic Patients: Comparison to Non-diabetic Children

In 1989 a nation-wide investigation of blood pressure and urinary albumin excretion rate (AER) was carried out in 506 boys and 441 girls with Type 1 diabetes (approximately 80 % of total) treated at 22 paediatric departments. In addition a reference population from 1979 consisting of 663 healthy non-diabetic children (334 boys, 329 girls) served as a control group with respect to blood pressure and body mass index. Microalbuminuria was defined as AER of 20–150 μg min^-1 in at least two out of three timed overnight urine collections and was diagnosed in 30 adolescents (16 boys, 14 girls). Five patients (3 boys, 2 girls) had overt proteinuria (AER: > 150μg min^-1). Age-related percentile charts based on one blood pressure reading were provided for normoalbuminuric diabetic patients and the healthy control group. The study revealed an increase in arterial blood pressure during the period of the pubertal growth spurt for the diabetic and non-diabetic group. The changes were most pronounced for systolic blood pressure. No statistically significant difference was observed in systolic and diastolic blood pressure between normoalbuminuric diabetic children and healthy control children. However, diabetic females aged 15–18 years had significantly higher diastolic blood pressure (75 ± 1 mmHg, n = 139, mean ± SE) than healthy control females (72± 1 mmHg, n = 155, p ± 0.01), and significantly (p ± 0.001) higher body mass index (diabetic females: 22.3± 0.2 kg m^-2 vs healthy females: 20.9± 0.2 kg m^-2, mean± SE). Boys aged from 15 to 18 years with Type 1 diabetes had significantly higher systolic blood pressure (123± 1 mmHg, n = 164) than girls (117± 1 mmHg, n = 139, p± 0.0001), while girls aged from 15 to 18 years had significantly higher diastolic blood pressure (75± 1 mmHg, n = 139) than boys (72± 1 mmHg, n = 72, p ± 0.01). Among the 30 adolescents with persistent microalbuminuria, 18 (10 boys, 8 girls) had diastolic blood pressure above the upper quartile for normoalbuminuric patients, while 2 out of 5 with macroalbuminuria had diastolic blood pressure above this limit. By multiple logistic regression the only risk determinants for elevated urinary albumin levels were age and diastolic blood pressure. These findings suggest that elevated arterial blood pressure is related to the increased prevalance of microalbuminuria observed in adolescents with Type 1 diabetes.     

The relationship of urinary albumin excretion rate to ambulatory blood pressure and erythrocyte sodium-lithium countertransport in NIDDM

Summary Increased erythrocyte sodium-lithium countertransport rate is found in non-diabetic subjects with essential hypertension, and in insulin-dependent diabetic subjects with nephropathy. However, relationships between these variables in non-insulin-dependent diabetic subjects are ill-defined. In order to characterise the relationships between blood pressure, urinary albumin excretion, and erythrocyte sodium-lithium countertransport, 66 subjects with non-insulin-dependent diabetes were studied. Urinary albumin excretion rate correlated with mean 24-h ambulatory systolic blood pressure (r=0.57; p<0.001), but not with sodium-lithium countertransport (r=0.06; p=0.31). No significant relationship was observed between 24-h systolic blood pressure and erythrocyte sodium-lithium countertransport (r = 0.16; p=0.17). The principal differences between microalbuminuric and normoalbuminuric subjects (albumin excretion rate >15 g·min^–1 [n=20], and <15 g·min^–1, [n=46]) were: higher 24-h systolic blood pressure (145.9 [16.8] mm Hg vs 131.9 [16.8] mm Hg; p=0.006), nocturnal heart rate (72.4 [8.9] vs 67.4 [8.9] beats·min^–1; p=0.042), and HbA₁ (11.3 [1.5]% vs 10.1 [2.0]%; p=0.028), and a longer median duration of diabetes (10.0 vs 5.0 years; p = 0.02). In contrast, there was no significant difference in sodium-lithium countertransport rate between microalbuminuric (0.41 [0.18] mmol·l^–1·h^–1) and normoalbuminuric subjects (0.39 [0.15] mmol·l^–1· h^–1; p=0.687). In multiple regression analysis controlling for race, age, body mass index and HbA₁, the significant determinants of albumin excretion rate were 24-h systolic blood pressure (B [regression coefficient]=0.029, SE[B] [standard error of B]=0.009, t=2.95, p=0.005), duration of diabetes (B=0.430, SE[B]=0.169, t=2.54, p=0.016) and male gender (B=–1.170, SE[B]=0.457, t=–2.56, p=0.015). In conclusion, albumin excretion rates in non-insulin-dependent diabetic subjects are linked to hypertension and glycaemic exposure, but show no relationship to erythrocyte sodium-lithium countertransport.Abbreviations IDDM Insulin-dependent diabetes mellitus - NIDDM non-insulin dependent diabetes mellitus - SLC sodium lithium countertransport - AER albumin excretion rate - B regression - SE coefficient; standard error of B     

Left Ventricular Hypertrophy in Non-insulin-dependent Diabetic Patients With and Without Diabetic Nephropathy

The aim of our cross-sectional case–control study was to evaluate putative mechanisms of the increased cardiac morbidity and mortality in NIDDM patients with or without diabetic nephropathy. Fifty-one NIDDM patients with diabetic nephropathy (38 males, age 61 ± 8 years, group 1), 53 NIDDM patients with normoalbuminuria (42 males, 61 ± 7 years, group 2), and 22 non-diabetic control subjects (15 males, 58 ± 8 years, group 3) were investigated. Previous antihypertensive treatment was withdrawn 2 weeks before the study. Left ventricular mass index (LVMI) and systolic function were determined by echocardiography. LVMI was elevated, mean ± SE, in group 1: 157 ± 6 g m⁻², and in group 2: 139 ± 7 g m⁻², as compared with group 3: 95 ± 5 g m⁻² (p < 0.001, for both), and in group 1 as compared with group 2 (p = 0.05). The prevalence of left ventricular hypertrophy (LVH) (LVMI > 131 g m⁻² in men and > 100 g m⁻² in women) was much higher in group 1: 75 % (95 % CI, 60–86), and group 2: 51 % (95 % CI, 37–65), as compared with group 3: 9 % (95 % CI, 1–29) (p < 0.001, for both), and in group 1 as compared with group 2 (p < 0.01). Shortening fraction of the left ventricle, % ± SE, was relatively reduced in group 1: 32.5 ± 1.1 %, and group 2: 33.4 ± 1.1 %, as compared with group 3: 41.2 ± 1.2 % (p < 0.01, for both). In a subgroup of 26 normoalbuminuric normotensive NIDDM patients, LVMI was higher than in 14 normotensive non-diabetic control subjects: 137 ± 10 g m⁻² vs 96 ± 7 g m⁻², respectively (p < 0.005). The prevalence of LVH was 42 % (95 % CI, 23–63) and 14 % (95 % CI, 2–43) (p = 0.07) in these two groups, respectively. In conclusion, normotensive and hypertensive NIDDM patients with and without diabetic nephropathy frequently suffer from LVH and relatively reduced systolic function which may constitute independent risk factors for fatal and non-fatal cardiac events. © 1997 John Wiley & Sons, Ltd.     

Plasma Lipoprotein Composition and Cholesteryl Ester Transfer from High Density Lipoproteins to Very Low Density and Low Density Lipoproteins in Patients with Non-insulin-dependent Diabetes Mellitus

We have examined cholesteryl ester transfer (CET) from HDL to low density and very low density lipoproteins (LDL and VLDL) and lecithin:cholesterol acyl transferase (LCAT) activity in plasma from 28 men with non-insulin-dependent diabetes mellitus (NIDDM) treated with diet alone or diet and sulphonylurea drugs and in 27 healthy non-diabetic controls. Patients and healthy subjects had similar LCAT activity, but CET was significantly higher in NIDDM 26.1 ± 11.5 μmol l⁻¹ h⁻¹) than in healthy men (17.8 ± 6.5 μmol l⁻¹ h⁻¹) (p = 0.001). Diabetic men also had higher CET compared to 15 healthy non-diabetic men (18.7 ± 5.6 μmol l⁻¹ h⁻¹) (p = 0.001) with similar serum lipids. CET activity was similar in patients treated with diet alone (24.8 ± μmol l⁻¹ h⁻¹) or with sulphonylureas (27.7 ± 15.8 μmol l⁻¹ h⁻¹). The Sf 0–12 fraction was significantly enriched with total cholesterol (p = 0.0001) and free cholesterol (p = 0.006) in diabetic subjects whether treated with diet alone or on sulphonylureas compared to the 15 non-diabetic controls matched for serum triglycerides. The free cholesterol/phospholipid, the free cholesterol/total protein and the free cholesterol/mass ratios were increased in the Sf 0–12 fraction in diabetic subjects (p < 0.01). These findings indicate that CET is accelerated in patients with NIDDM and that this may be due to the altered composition of acceptor lipoproteins.     

Renal kallikrein in diabetic patients with hypertension accompanied by nephropathy

Summary We measured the 24-h excretion of urinary kallikrein in 27 patients with Type 2 (non-insulin-dependent) diabetes and in 10 normal control subjects. Mean (± SD) kallikrein excretion in diabetic patients with nephropathy (6.2±2.4 naphthyl units (NU)/day,n=13) was significantly lower than in control subjects (12.8±3.4NU/day,p<0.01) and in diabetic patients without nephropathy (9.4±3.4NU/day,n=14,p<0.05). Kallikrein excretion in hypertensive diabetic patients with nephropathy (5.1±1.6 NU/day,n=8) was significantly lower (p<0.05) than in normotensive patients with nephropathy (8.3±2.1 NU/day,n=5). There were no significant differences in kallikrein excretion rate (24-h excretion of urinary kallikrein/24-h creatinine clearance) among control subjects (9.9±4.3 NU/ml), diabetic patients with (9.0±3.2 NU/ml) and without (9.3±3.5 NU/ml) nephropathy. However, kallikrein excretion rate in hypertensive diabetic patients with nephropathy (7.7±3.3 NU/ml) was significantly lower (p<0.05) than in normotensive diabetic patients with nephropathy (11.8 ±2.0 NU/ml,n=10). Respective basal and post-stimulated (with intravenous furosemide 40 mg plus 60 min ambulation) plasma aldosterone concentrations measured in control subjects and in hypertensive diabetic patients with nephropathy were similar and increased to the same extent in the 2 groups (5.5±3.2 versus 5.3±3.2 and 9.3±2.6 versus 10.5±3.4 ng/ml), although the respective plasma renin activity tended to be lower in diabetic patients than in control subjects (0.7±0.6 versus 1.3±0.9 and 1.8±1.8 versus 3.0±2.6 ng⁻¹ · ml⁻¹ · h⁻¹). The results indicate that urinary kallikrein excretion is decreased in hypertensive diabetic patients with nephropathy, and that the decrease might not be attributable to an altered renin-aldosterone system.     

Assessment of insulin sensitivity and secretion with the labelled intravenous glucose tolerance test: improved modelling analysis

Summary A new modelling analysis was developed to assess insulin sensitivity with a tracer-modified intravenous glucose tolerance test (IVGTT). IVGTTs were performed in 5 normal (NGT) and 7 non-insulin-dependent diabetic (NIDDM) subjects. A 300 mg/kg glucose bolus containing [6,6-²H₂]glucose was given at time 0. After 20 min, insulin was infused for 5 min (NGT, 0.03; NIDDM, 0.05 U/kg). Concentrations of tracer, glucose, insulin and C-peptide were measured for 240 min. A circulatory model for glucose kinetics was used. Glucose clearance was assumed to depend linearly on plasma insulin concentration delayed. Model parameters were: basal glucose clearance (Cl_b), glucose clearance at 600 pmol/l insulin concentration (Cl₆₀₀), basal glucose production (P_b), basal insulin sensitivity index (BSI = Cl_b/basal insulin concentration); incremental insulin sensitivity index (ISI = slope of the relationship between insulin concentration and glucose clearance). Insulin secretion was calculated by deconvolution of C-peptide data. Indices of basal pancreatic sensitivity (PSI_b) and first (PSI₁) and second-phase (PSI₂) sensitivity were calculated by normalizing insulin secretion to the prevailing glucose levels. Diabetic subjects were found to be insulin resistant (BSI: 2.3 ± 0.6 vs 0.76 ± 0.18 ml · min^–1· m^–2· pmol/l^–1, p < 0.02; ISI: 0.40 ± 0.06 vs 0.13 ± 0.05 ml · min^–1· m^–2· pmol/l^–1, p < 0.02; Cl₆₀₀: 333 ± 47 vs 137 ± 26 ml · min^–1· m^–2, p < 0.01; NGT vs NIDDM). P_b was not elevated in NIDDM (588 ± 169 vs 606 ± 123 μmol · min^–1· m^–2, NGT vs NIDDM). Hepatic insulin resistance was however present as basal glucose and insulin were higher. PSI₁ was impaired in NIDDM (67 ± 15 vs 12 ± 7 pmol · min^–1· m^–2· mmol/l^–1, p < 0.02; NGT vs NIDDM). In NGT and in a subset of NIDDM subjects (n = 4), PSI_b was inversely correlated with BSI (r = 0.95, p < 0.0001, log transformation). This suggests the existence of a compensatory mechanism that increases pancreatic sensitivity in the presence of insulin resistance, which is normal in some NIDDM subjects and impaired in others. In conclusion, using a simple test the present analysis provides a rich set of parameters characterizing glucose metabolism and insulin secretion, agrees with the literature, and provides some new information on the relationship between insulin sensitivity and secretion. [Diabetologia (1998) 41: 1029–1039] Received: 17 September 1997 and in final revised form: 28 April 1998     

Abnormal myocardial kinetics of 123I-heptadecanoic acid in subjects with impaired glucose tolerance

Summary Increased triglyceride accumulation has been observed in the diabetic heart, but it is not known whether the abnormalities in myocardial fatty acid metabolism differ between insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetic patients or whether they are present even prior to overt diabetes. Therefore, we studied myocardial fatty acid kinetics with single-photon emission tomography using ¹²³I-heptadecanoic acid (HDA) in four groups of men: impaired glucose tolerance (IGT) (n = 13, age 53 ± 2 years, mean ± SEM), IDDM (n = 8, age 43 ± 3 years), NIDDM (n = 10, age 51 ± 2 years) and control subjects (n = 8, age 45 ± 4 years). Echocardiography and myocardial perfusion scintigraphy (IGT and NIDDM groups) were performed to study cardiac function and flow. In the IGT subjects, myocardial HDA beta-oxidation index was reduced by 53 % (4.6 ± 0.4 vs 9.7 ± 1.0 μmol · min^–1· 100 g^–1, p < 0.01) and HDA uptake by 34 % (3.7 ± 0.2 vs 5.6 ± 0.3 % of injected dose 100 g, p < 0.01) compared with the control subjects. The fractional HDA amount used for beta-oxidation was lower in the IGT compared with the control subjects (43 ± 4 vs 61 ± 4 %, p < 0.05). NIDDM patients also tended to have a lowered HDA beta-oxidation index, whereas IDDM patients had similar myocardial HDA kinetics compared to the control subjects. Myocardial perfusion imaging during the dipyridamole-handgrip stress was normal both in the IGT and NIDDM groups, indicating that abnormal myocardial perfusion could not explain abnormal fatty acid kinetics. In conclusion, even before clinical diabetes, IGT subjects show abnormalities in myocardial fatty acid uptake and kinetics. These abnormalities may be related to disturbed plasma and cellular lipid metabolism. [Diabetologia (1997) 40: 541–549] Received: 26 August 1996 and in revised form: 21 November 1996